Cisplatin Resistance and Transcription Factors - Ingenta Connect

Curr. Med. Chem. - Anti-Cancer Agents, 2005, 5, 15-27

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Cisplatin Resistance and Transcription Factors Takayuki Torigoe1, Hiroto Izumi1, Hiroshi Ishiguchi1, Yoichiro Yoshida1, Mizuho Tanabe1, Takeshi Yoshida1, Tomonori Igarashi1, Ichiro Niina1, Tetsuro Wakasugi1, Takuya Imaizumi1, Yasutomo Momii1, Michihiko Kuwano2 and Kimitoshi Kohno1,* 1

Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka 807-8555, Japan and 2Research Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, Kurume University, Kurume, Fukuoka 830-0011, Japan. Abstract: Cisplatin is one of the most potent and widely used anti-cancer agents in the treatment of various solid tumors. However, the development of resistance to cisplatin is a major obstacle in clinical treatment. Several mechanisms are thought to be involved in cisplatin resistance, including decreased intracellular drug accumulation, increased levels of cellular thiols, increased nucleotide excision-repair activity and decreased mismatch-repair activity. In general, the molecules responsible for each mechanism are upregulated in cisplatin-resistant cells; this indicates that the transcription factors activated in response to cisplatin might play crucial roles in drug resistance. It is known that the tumor-suppressor proteins p53 and p73, and the oncoprotein c-Myc, which function as transcription factors, influence cellular sensitivity to cisplatin. So far, we have identified several transcription factors involved in cisplatin resistance, including Y-box binding protein-1 (YB-1), CCAAT-binding transcription factor 2 (CTF2), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143) and mitochondrial transcription factor A (mtTFA). Two of these—YB-1 and ZNF143—lack the high-mobility group (HMG) domain and can bind preferentially to cisplatin-modified DNA in addition to HMG domain proteins or DNA repair proteins, indicating that these transcription factors may also participate in DNA repair. In this review, we summarize the mechanisms of cisplatin resistance and focus on transcription factors involved in the genomic response to cisplatin.

Key Words: ATF4, cisplatin, c-Myc, CTF2, mtTFA, p53/p73, YB-1, ZNF143. INTRODUCTION cis-diamminedichloroplatinum (II) (cisplatin) plays a crucial role in the treatment of many solid tumors. The mechanisms of cisplatin-induced cytotoxic activity are not completely understood; however, the therapeutic effect of cisplatin is believed to result from the formation of covalent adducts with DNA [1, 2]. Cisplatin has been shown to cause the formation of intrastrand cross-links between adjacent purines in genomic DNA. The major cisplatin cross-links are intrastrand 1, 2-d(GpG) and d(ApG); DNA damage signals then induce apoptosis in various solid tumor cells [1, 2]. Cisplatin treatment induces not only DNA damaging stress, but also oxidative and endoplasmic reticulum (ER) stresses [3, 4]. This, along with the other available evidence, demonstrates the highly complex nature of cellular sensitivity to cisplatin. Of the induced genomic responses, anti-apoptotic defenses are activated simultaneously with apoptotic signaling [5]. The major limitation to clinical treatment is the development of cisplatin resistance by tumors through these mechanisms, which include efflux and detoxification of cisplatin, and DNA repair. Other genes that are differentially expressed in association with acquired cisplatin resistance have been identified, including *Address correspondence to this author at the Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan; Tel: +81-93-691-7423; Fax: +81-93-692-2766; E-mail: [email protected] 1568-0118/05 $50.00+.00

cytochrome oxidase I, ribosomal protein S28, elongation factor 1α, α-enolase, stathmin and HSP70 [6]. Understanding the molecular basis of cisplatin-induced genomic responses in cisplatin resistance is therefore important for determining clinical strategies. Many genes have been identified that affect cancer cells during programmed cell death following various genotoxic stresses. The activation of the typical tumor-suppressor proteins p53 and p73 can result in cell-cycle arrest, DNA repair or apoptosis [7, 8]. Loss of p53 function confers resistance to cisplatin in various human cancer cell lines [9], whereas overexpression of p73 is associated with cisplatin resistance [10]. Recently, it has been shown that codon 72 polymorphic variants of p53 display altered mitochondrial translocation and apoptotic potential [11]. Furthermore, mutations in the p53 gene have been widely detected in various human cancer cells, indicating that p53 might be critical in determining drug sensitivity [12]. However, it is not clear how many transcription factors play significant roles in cisplatin-induced stress responses and drug sensitivity. We believe that transcription factors for genes involved in cisplatin resistance are often activated by DNA damage; therefore, identification and characterization of cisplatin-induced transcription factors might provide a shortcut to deciphering cisplatin sensitivity and resistance in clinical treatment. In this article, we describe the main mechanisms of cisplatin-induced apoptosis and cisplatin resistance, and discuss the transcription factors involved in resistance to © 2005 Bentham Science Publishers Ltd.

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cisplatin: p53/p73, c-Myc, YB-1, CTF2, ATF4, ZNF143 and mtTFA. Additionally, we refer to the potential responses of some other transcription factors, including octamer transcription factor Oct1 and the zinc-finger protein Sp1, to anti-cancer agents. CISPLATIN-INDUCED APOPTOSIS DNA is the primary target of cisplatin in cancer cells and one of the major cytotoxicities of cisplatin is thought to be caused by the formation of cisplatin–DNA adducts. Cisplatin binds preferentially to the N7 atom of guanine residues, especially in regions of two or more consecutive guanines. Thus, the major cisplatin cross-links are intrastrand 1, 2d(GpG) and d(ApG), whereas the minor cross-links include intrastrand 1, 3-d(GpNpG), as shown in Fig. (1) [1, 2]. Intrastrand 1, 2-d(GpG) and d(ApG) provide the strongest basis for cisplatin-induced cytotoxicity. Cisplatin is hydrolyzed and equilibrium is maintained between cisplatin (the Cl-Cl species; (NH3)2PtCl2), the charged species (the H2O-Cl species; [(NH3)2PtCl(H2O)]+), and the neutral species (the OH-Cl species; (NH3)2PtCl(OH)) in physiological conditions of intracellular pH and chloride concentration. Charged species under low Cl– and/or low pH conditions, such as the H2O-Cl and H2O-H2O species, are more reactive than the Cl-Cl species because of their nucleophilic properties (Fig. (2)). Thus, intracellular Cl– and pH levels could modulate the cytotoxicity of cisplatin [13]. Cisplatin can induce two major distinct apoptotic pathways via various stress signalings: the first is p53-dependent mitochondrial apoptosis, which begins with translocation of the p53-induced Bax from the cytosol to the mitochondria, followed by cytochrome c release and activation of caspase-9 and -3 [14]; the second is the Fas/Fas ligand-dependent caspase-8-induced apoptotic cascade [15].

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Mitogen-activated protein kinase (MAPK) signaling pathways, including the extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) pathways, play important roles in cellular responses to stress conditions, including various anti-cancer agents [16]. The ERK signaling pathway is involved in the regulation of cell growth, differentiation, proliferation and survival. By contrast, the p38 and JNK signaling pathways are stress dependent and have apoptotic regulatory functions. Cisplatininduced activation of ERK signaling could contribute to resistance to cisplatin [17]; conversely, induction of the JNK/p38 signaling pathway in response to cisplatin induced apoptosis via Fas ligand induction in ovarian cancer cells [15]. However, Wang et al. have shown that ERK activation plays an important role in the cisplatin-induced apoptosis of Hela cells [3]. These results suggest that such differential effects of MAPK signals in response to drug-induction could reflect cell-type specificity. The functions of the JNK signaling pathway in apoptosis induced by cisplatin also remain unclear, as does ERK signaling [15, 18]. Further investigation is necessary to probe the exact cisplatininduced mechanisms of these signaling pathways. Initially, DNA damage signals induced by cisplatin can activate so-called sensor kinases. It was reported that cisplatin induces the phosphatidylinositol 3-kinase (PI3K)/ AKT signaling pathway to mediate p21 expression, suggesting that it might be involved in cell-cycle regulation; however, inhibition of the PI3K/AKT pathway had no influence on sensitivity to cisplatin [19]. However, it was recently reported that AKT phosphorylates the X-linked inhibitor of apoptosis protein (XIAP) and is involved in cisplatin resistance [20]. Moreover, cisplatin could phosphorylate p53 at serine 15 and induce p53 downstream genes via activation of ataxia telangiectasia mutated and Rad3related protein (ATR) kinase [21]. ATR signaling has also

Fig. (1). Schematic diagram of cisplatin-DNA adducts. Intrastrand 1, 2-d(GpG) and d(ApG) are the major cisplatin cross-links (85-90% of total lesions), whereas the minor cross-links is intrastrand 1, 3-d(GpNpG). The major lesions provide the strongest basis for cisplatin-induced cytotoxicity.

Cisplatin Resistance and Transcription Factors

Curr. Med. Chem. – Anti-Cancer Agents, 2005, Vol. 5, No. 1 17

Fig. (2). Formation of intracellular cisplatin. The equilibrium of cisplatin is affected by physiological conditions of intracellular pH and chloride concentration. The charged species under low Cl– and/or acidic conditions (the H2O-Cl, H2O-OH and H2O-H2O species) are the most active forms.

been linked to the MAPK signaling cascade [22]. Another kinase, the c-Abl tyrosine kinase, is also activated by cisplatin. This kinase phosphorylates p73 and induces apoptosis [23]. The c-Abl pathway is also associated with the JNK signaling pathway, which is a member of the MAPK family [24]. The evidence therefore suggests that DNA damage signals might undergo crosstalk with each other. Protein phosphatase is also involved in the cisplatininduced signaling pathway through regulating the cellular phosphorylation state. Nuclear Src homology 2 domaincontaining tyrosine phosphatase (SHP-2) was constitutively associated with c-abl and its phosphatase activity was significantly enhanced in response to DNA damage. It was reported that cells lacking SHP-2 showed markedly decreased apoptosis in response to DNA-damaging agents, such as cisplatin and γ-irradiation [25]. Furthermore, cisplatin has been shown to interact with the tumorsuppressor phosphatase and tensin homolog (PTEN), which plays an important role in cell growth and apoptosis [26]. The enzymatic activity of protein tyrosine phosphatases (PTPs) containing PTEN is often regulated by a redox system, including thioredoxin-1 [27, 28]. Apoptosis signalregulating kinase 1 (ASK1) is a MAPK kinase kinase that activates p38 and JNK cascades, and is activated in response to oxidative stress [29]. Protein phosphatase 5 interacts with ASK1 and inhibits its activity [30]. These results provide

evidence that protein phosphatase is an important modulator of apoptosis through cisplatin-induced DNA damage and oxidative stress, and that it contributes to drug sensitivity. Reactive oxygen species (ROS) are produced upon various stress stimulations—including ultraviolet (UV) irradiation and cytotoxic agents such as cisplatin—and are closely involved in stress-induced apoptosis. ROS production can enhance sensitivity to cisplatin through activation of the JNK or p38 pathways [31], or through Fas aggregation [32]. Furthermore, it has been recently reported that cisplatin could induce apoptosis in the absence of DNA damage, through ER stress [4]. Cisplatin induced the activation of the calcium-dependent protease calpain, which activated caspase-3 and ER-specific caspase-12 in cytoplasts [4]. These data suggest that the ER might be the non-nuclear target of cisplatin. Cisplatin-induced apoptotic pathways are complicated, as cisplatin might cause different stresses, such as DNA damaging, oxidative and ER stresses. Various cisplatininduced stress signals can activate each pathway through specific transcription factors that act as the ultimate drug targets. Cell death or survival in response to cisplatin might be dependent on the relative intensity of, and the crosstalk between, these signal pathways. Fig. (3) shows a schematic summary of cisplatin-induced cellular signaling involved in cell death and survival. Further studies will lead to a better

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Fig. (3). Schematic summary of cisplatin-induced damaging signals. Cisplatin induces different damaging signals, such as DNA damaging, oxidative and ER damaging stresses. These stresses can activate each pathway through specific phosphorylation cascades, which include transcription factors as the ultimate targets. The fate of cancer cells in cisplatin treatment is determined by the relative intensity of, and the crosstalk between, these signaling pathways.

understanding of the mechanisms involved in cisplatininduced apoptosis. MECHANISMS OF CISPLATIN RESISTANCE The development of cisplatin resistance by tumor cells is a major clinical limitation in cancer chemotherapy. This resistance might arise due to changes in the biochemical pharmacology of cisplatin. Cisplatin resistance is induced through various mechanisms, including the reduction of cisplatin accumulation inside cancer cells [5]. One of the several possible efflux pumps for cisplatin is the multidrug resistance-associated protein 2 (MRP2; also designated cMOAT). MRP2 is a member of the MRP gene family and these ABC membrane proteins have been connected with the efflux of various drugs [33]. A recent study has shown that expression of MRP2 coincides with resistance to cisplatin [34] and Koike et al. have demonstrated that cisplatin sensitivity is increased by antisense MRP2 constructs [35]. These data give an insight into the relationship between MRP2 expression and drug resistance. Moreover, the copper

transporters ATP7A and ATP7B have been shown to be involved in cisplatin efflux [36], and have potential as clinical markers in ovarian cancer specimens [37, 38]. However, the P-glycoprotein, which is a membrane channel encoded by the multidrug resistance 1 (MDR1) gene, has been reported not to participate in cisplatin resistance [39]. In another mechanism of resistance, increased activity of intracellular pathways of thiol production—including glutathione (GSH), metallothionein and thioredoxin—can contribute to the detoxification of cisplatin [5]. A small fraction of the intracellular cisplatin can bind to genomic DNA. However, a major fraction, about 60% of the intracellular cisplatin, is conjugated with GSH [40]. GSH is one of the most abundant SH-containing molecules, which can interact with cisplatin through the catalytic action of glutathione S-transferase π (GSTπ). GS-platinum complexes, which show inactivated cytotoxicity, are discharged from cancer cells via the glutathione conjugate export pump (GSX pump) [1, 2]. GSTπ and γ-glutamylcysteine synthetase ( γGCS), which is the enzyme involved in GSH biosynthesis,


were also shown to be associated with cisplatin resistance [41, 42]. Metallothionein is rich in thiol-containing cysteine and is presumed to function in the detoxification of heavy metals such as cadmium. Overexpression of metallothionein has been observed in cisplatin-resistant cell lines [43]. Thioredoxin, which is another intracellular thiol, is a redoxactive protein induced by various stresses and secreted from cells. Cellular levels of thioredoxin, thioredoxin reductase and glutaredoxin are associated with cisplatin resistance, as are GSH and metallothionein [5, 44]. The glutathione adducts, which are GS-platinum complexes, inhibit the thioredoxin and glutaredoxin systems; thus, these results are consistent with the correlation between increased thioredoxin and cisplatin resistance [45]. Moreover, it has been recently reported that thioredoxin, acting as a downstream effector of Smad7; inhibitor of transforming growth factor (TGF)-β1 signaling, could suppress cisplatin-induced apoptosis in pancreatic cancer [46]. Reduced thioredoxin is also an inhibitor of ASK1 [29], and peroxiredoxin that is dependent upon thioredoxin activity might protect cancer cells from apoptosis caused by cisplatin-induced oxidative stress [47]. The cytotoxicity of cisplatin is ascribed to the formation of cisplatin-DNA adducts, and to the induction of DNA damage signals and apoptosis. The following damagerecognition proteins have been identified: HMG domain proteins (high-mobility group 1 and 2 (HMG1/2), mtTFA and hUBF); transcription factors lacking an HMG domain (TATA-binding protein (TBP), YB-1 and ZNF143); nucleotide excision repair (NER) proteins (XPE, XPA); and mismatch repair (MMR) proteins (hMutSα and hMSH2) (Table (1) [48-57]). These proteins can recruit repair complexes to damaged regions or shield them by inhibiting DNA damage signals. The NER system is a vital pathway in the removal of cisplatin-DNA adducts and in the repair of DNA damage. First, damage-recognition proteins, such as XPA, detect cisplatin-DNA adducts. Then, XPG and ERCC1/XPF complexes make 3′ and 5′ incisions, respectively. Cisplatininduced DNA damage regions are excised and these gaps are repaired in a proliferating cell nuclear antigen (PCNA)dependent manner [2]. Cellular defects in the NER system have resulted in hypersensitivity to cisplatin [1, 2, 5] and NER related proteins, such as ERCC1 and XPA, have been overexpressed in cisplatin-resistant ovarian cancers [58, 59]. Recently, it has been shown that transcription-coupled NER is more closely related to cisplatin resistance than global genomic NER [60]. ERCC1 was shown to physically interact with a MMR protein, MSH2; these proteins might act Table 1.


cooperatively in cisplatin resistance [61]. The MMR system consists of various proteins, including MSH2, MSH3, MSH6 and MLH1. A defective MMR pathway in cisplatin resistance is associated with microsatellite instability [62] and these repair proteins were also demonstrated to contribute to drug resistance [63]. These data represent NER and MMR pathways as critical mechanisms in cisplatin resistance. The Fanconi anemia-BRCA1 pathway also regulates cisplatin sensitivity [64, 65]. BRCA1 colocalizes at DNA damage lesions and interacts with various DNA repair proteins residing within a large DNA repair protein complex known as the BRCA1-associated genome-surveillance complex; this indicates that BRCA1 is a critical component of multiple repair pathways [66]. However, there is no evidence that BRCA1 directly binds to cisplatin-modified DNA. A recent report from Wang and Lippard has demonstrated that cisplatin treatment could induce the phosphorylation of histone H3 at serine 10, mediated by the p38 signaling pathway and acetylation of histone H4 [67]. These chromatin modifications are thought to be involved in drug resistance, because they increase the accessibility of DNA for transcription factors and DNA repair proteins. In general, tumor cells upregulate glycolysis and can grow in a severe microenvironment with hypoxia and/or acidosis; therefore, pH regulators are upregulated in highly proliferative cancer cells to avoid intracellular acidification [68, 69]. We have previously shown that subunit genes of one of the pH regulators, vacuolar H+-ATPase (V-ATPase), are induced by cisplatin treatment and are overexpressed in cisplatin-resistant cell lines [70]. Intracellular pH was markedly higher in cisplatin-resistant cell lines than in sensitive parental cell lines. Furthermore, DNA-binding activity of cisplatin was markedly increased in acidic conditions [13, 70]. The DNA topoisomerase II inhibitor TAS-103, which can induce intracellular acidosis [71], also enhanced expression of the V-ATPase subunit genes [72]. In addition, we found that combining the V-ATPase inhibitor bafilomycin A1 with cisplatin or TAS-103 could enhance drug-induced apoptosis in cancer cells [70, 72]. Thus, elevated expression of pH regulators, such as V-ATPase subunit genes, contributes to the avoidance of apoptosis induced by intracellular acidosis and/or the drug cytotoxicity of cisplatin and TAS-103. TRANSCRIPTION FACTORS CISPLATIN RESISTANCE

INVOLVED

Resistance to cisplatin is orchestrated via several mechanisms (as described above). These might be regulated

Cisplatin-Induced Damage-Recognition Proteins

Transcription factors possessing an HMG domain Transcription factors lacking an HMG domain HMG domain proteins Repair proteins Chromatin protein * indicates transcription factors focused on in this article.

IN

Protein

References

mtTFA*, UBF TBP, YB-1*, ZNF143* HMG1/2, SRY, SSRP1 XPE, XPA, MutSα, MSH2 Histone H1

49, 50 51-53 48, 142, 143 54-57 144

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by various transcription factors, which are often activated in response to cisplatin treatment. We now realize that molecular mechanisms of DNA damage signaling and cisplatin resistance are much more complex than was previously predicted. Transcription factors participate not only in gene expression, but also in DNA repair and apoptosis at the end of all signal transduction and stressinduced pathways. Various classified molecules mutually interact and function in nuclei; these interaction profiles might be altered by DNA damage, indicating that analysis of protein-interaction profiles is critical for future post-genomic research in cancer treatment. Fig. (4) illustrates DNA damage signaling and the ways in which this pathway might be associated with drug resistance, DNA repair and apoptosis. Cisplatin-induced transcription factors are closely involved in cisplatin resistance, and investigation of their mechanisms of action might allow us to overcome drug resistance. Furthermore, these transcription factors might be

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promising potential targets for clinical cancer treatment. Table (2) shows a summary of transcription factors and interacting molecules involved in cisplatin resistance. p53/p73 The p53 tumor-suppressor gene family proteins p53 and p73 are central to the cellular response to DNA damage. These proteins accumulate in nuclei after DNA damage and control cell proliferation [73, 74]. Cisplatin treatment can stabilize p53 through ATR- and MAPK-induced phosphorylation of p53 at serine 15; this treatment also induces p53 downstream genes [21, 75]. Several genes transcriptionally controlled by p53 have been identified, including the CDK inhibitor p21/Waf1/Cip1 gene, the growth arrest and DNA damage-inducible GADD45 gene and the pro-apoptotic bax gene [73]. Another significant role of p53 is its possible involvement in DNA repair. p53 preferentially associates

Fig. (4). Flow diagram illustrating the cellular effects of cisplatin. Cisplatin treatment can activate various classified molecules, including DNA damage-recognition factors, DNA repair factors and transcription factors involved in cisplatin resistance via cisplatin-induced signal transductions. These factors mutually interact and function in nuclei, and interaction profiles might be altered by DNA damage. Thus, these molecular interactions are closely involved in genome stability, DNA damage tolerance and damage-induced apoptosis. The analysis of protein-interaction profiles is critical for future post-genomic research in cancer chemotherapy.


Table 2.


Transcription Factors Involved in Cisplatin Sensitivity

Transcription factor

Target gene

Interacting protein involved in drug resistance

p53/p73

p21, GADD45, Bax

Myc/Max YB-1*

Myc/Max, YB-1 MDR1, cyclin A/B1, TopoIIα, Fas, PTP1B, GPX1 HMG1 ZNF143, CHOP mtTFA, MRP S11

c-Myc [83], YB-1 [85], CTF2 [104], TBP [73], mtTFA [127], HMG1 [105], XPB [76], XPD [76] p53/p73 [83] p53 [85], PCNA [52], MSH2 [92], Ku80 [92], DNA polymerase δ [92], WRN protein [92] p53/p73 [104] Nrf1/2 [110, 111] unknown p53 [127] Sp1 [145], HMG2 [136] p53 [137], Oct1 [145], c-Jun [137], NF-κB [146], TBP [146], p38 [147], BRCA1 [137]

CTF2 ATF4 ZNF143* mtTFA* Oct1 Sp1

ATP6L (V-ATPase c subunit), TrxR ATP6L (V-ATPase c subunit), DNA-PKcs, VEGF, TrxR

* indicates specific recognition of cisplatin-modified DNA Bracketed numbers indicate references.

with damaged DNA and interacts with DNA repair proteins, such as XPB and XPD [76]. Additionally, wild-type p53, but not mutant p53, has been demonstrated to exert intrinsic 3’→5’ exonuclease activity [77]. Cancer cells carrying lossof-function mutants of p53 are also less sensitive to anticancer agents [12]. p73 possesses structural and functional similarities to p53, and is able to activate p53-responsive genes and induce apoptosis. p73 was initially cloned from neuroblastoma cell lines and is involved in the development of the central nervous system [74]. The c-Abl tyrosine kinase can activate p73 by phosphorylating the p73 protein and induce apoptosis in response to DNA damage [23]. However, it has recently been reported that p73α overexpression is associated with resistance to DNA damaging agents [10]. These findings indicate that the major roles of p73 remain unclear and might be different from those of p53 in tumor cells. Further investigation is necessary to understand the functional differences between p53 and p73 in drug resistance. c-Myc The oncoprotein c-Myc is a transcription factor that binds to E-box and transactivates various genes. c-Myc has been shown to function in many cellular processes, including cell proliferation, differentiation and transformation [78]. However, c-Myc is also able to induce apoptosis under certain conditions, such as deprivation of survival factors or treatment with anti-cancer agents [79, 80]. The mechanisms of c-Myc-induced cell growth and apoptosis remain unclear. A recent report has shown that c-Myc downregulation is involved in cisplatin sensitivity in human melanoma cells [81]. Low expression of c-Myc or c-Myc downregulation by antisense oligonucleotides resulted in increased susceptibility to cisplatin, via glutathione depletion [82]. We have previously demonstrated that p73 interacts with c-Myc to regulate gene expression via E-box binding [83]. Furthermore, p73 stimulated the interaction of Max; the dimerization partner of the Myc oncoprotein with c-Myc and promoted binding of the c-Myc/Max complex to its target

DNA. Our findings might help explain the complicated functions of c-Myc in drug resistance of cancer cells. Y-Box Binding Protein-1 (YB-1) YB-1 is the most highly evolutionarily conserved nucleic-acid-binding protein and is a member of the coldshock domain (CSD) protein superfamily. It functions in various biological processes, including transcriptional regulation, translational regulation, DNA repair, drug resistance and cell proliferation [84, 85]. YB-1 is a transcription factor, which was first identified by its ability to bind to the inverted CCAAT box (Y-box) of the MHC class II promoter. YB-1 has also been shown to regulate the expression of various genes through a Y-box in promoter regions, including MDR1, cyclin A/B1, DNA topoisomerase IIα, Fas and Protein tyrosine phosphatases 1B (PTP1B) [8587]. YB-1 comprises three domains: a variable N-terminal domain; a highly conserved nucleic-acid-binding domain (the CSD); and a C-terminal basic and acidic amino-acid cluster domain (called a B/A repeat) [84, 85]. The Nterminal domain is thought to be a trans-activation domain and the CSD has an affinity for double-stranded DNA in vitro. The C-terminal region functions as either a nucleic acid-binding domain or a protein-protein interaction domain; the C-terminal domain also has a strong affinity for singlestranded DNA/RNA in vitro and is involved in dimerization [88]. YB-1 has pleiotropic functions, which are conferred through molecular interactions with a diverse range of proteins. It regulates human gene expression via interactions with transcription factors, including p53, p65, AP2, CTCF and Smad3 [85, 89]. YB-1 also interacts with the RNAbinding proteins IRP2 and hnRNPK to regulate mRNA translation and splicing, respectively [90, 91]. An examination of its physical partners might help to elucidate the integrated functions of YB-1. YB-1 might be one of the components necessary for DNA repair. We previously reported that YB-1 preferentially binds to cisplatin-modified DNA, similarly to HMG domain

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proteins [52]. This is the first evidence that a sequencespecific transcription factor can recognize cisplatin-modified DNA. YB-1 interacts with PCNA, which is necessary for nucleotide-excision repairs [52], in addition to DNA repair proteins such as MSH2, DNA polymerase δ, Ku80 and WRN protein [92]. YB-1 also possesses 3′→5′ exonuclease and endonucleolytic activities [88, 92], and is thus thought to be involved in base-excision repair. Furthermore, YB-1 preferentially binds to RNA containing 8-oxoguanine, which suggests that it might be able to detect damaged RNA molecules [93]. YB-1 is mainly localized in the cytoplasm. When cells are challenged with anti-cancer agents, hyperthermia or UV irradiation, YB-1 is immediately translocated from the cytoplasm to the nucleus [85, 94]. We have demonstrated that promoter activity of the MDR1 gene increases in response to various environmental stresses in a Y-boxdependent manner [95]. We have also shown that YB-1 is overexpressed in human cancer cell lines, which are resistant to cisplatin, and that cisplatin sensitivity is increased by antisense YB-1 constructs [96]. Moreover, the disruption of one allele of the YB-1 gene increased sensitivity to cisplatin and mitomycin C in mouse embryonic stem cells [97]. Additionally, increased YB-1 expression in clinical specimens has been reported to be significantly correlated with tumor progression and poor prognosis in lung cancer, ovarian cancer, prostate cancer and synovial sarcoma [85, 98, 99]. Interestingly, it has been shown that YB-1 can recognize the selenocysteine insertion-sequence element in glutathione peroxidase (GPX1) gene transcripts, suggesting that increased YB-1 might enable the effective translation of selenoproteins under cisplatin-induced oxidative stress [100]. These data indicate that YB-1 might have the capacity to protect the genome from DNA damaging agents in cancer cells, might play an important role in drug resistance and, thus, might be a new molecular target in cancer treatment. CCAAT-Binding Transcription Factor 2 (CTF2) The CCAAT-binding transcription factor/nuclear factor I (CTF/NF-I) family of ubiquitous transcription factors was initially discovered as part of an adenovirus-DNA replication complex. CTF/NF-I group proteins recognize the sequence TTGGC(N5)GCCAA and are involved in the transcriptional regulation of various genes [101, 102]. CTF2 is one of four different splice variants of the CTF/NF-I protein. We have previously determined that CTF2 is overexpressed in cisplatin-resistant cells, and that overexpression of this transcription factor might be responsible for the transactivation of the HMG1 gene [103]. p53 and p73 physically interact with CTF2 and reciprocally regulate HMG1 gene expression; p73α upregulates the activity of the HMG1 gene promoter and enhances the DNA binding activity of CTF2, although p53 does not [104]. HMG1 (also designated HMGB1) and HMG2—the nonhistone chromosomal proteins—are ubiquitously expressed in higher eukaryotes, function as class II transcription factors and preferentially bind to cisplatin-modified DNA [48]. Furthermore, physical interaction of HMG1 with p53 enhances binding of cisplatin-modified DNA [105]. HMG1 and HMG2 have been implicated in cisplatin

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resistance [106, 107]. CTF2 might thus be a potential target in overcoming cisplatin resistance, because it could regulate HMG1 gene expression in cancer cells. However, Wei et al. demonstrated recently that HMG1 knockout of mouse embryonic fibroblasts has no effect on cisplatin sensitivity [108]. Further studies are needed to establish the mechanisms involving CTF2 and HMG1/2 in cisplatin resistance. Activating Transcription Factor 4 (ATF4) ATF4 is a member of the ATF/cyclic AMP-responsive element-binding (CREB) family of transcription factors, and is widely expressed in a variety of tissues and tumor cell lines. It has been reported previously that ATF4 forms a homodimer in vitro and binds to the consensus ATF/CRE site TGACGTCA [109]. Various stress-inducible genes, including DNA repair genes, contain an ATF/CRE site in their promoter regions. ATF4 interacts with nuclear-factor erythroid 1 (Nrf1)- and Nrf2-related factors, which are recruited to the antioxidant-response element and regulate the expression of genes encoding enzymes with antioxidant or detoxification functions [110, 111]. Moreover, ATF4-null cells show impaired expression of genes involved in glutathione biosynthesis and resistance to oxidative stress [112]. Additionally, ATF4 participates in ER stress-induced gene expression and transactivates ER stress response-related protein; CHOP (a CCAAT/enhancer-binding protein (C/EBP) family protein) in response to amino-acid starvation [113]. Thus, these data might provide insights into the relation between ATF4 expression and cisplatin resistance. Transcription profiling by cDNA arrays that are inducible by genetic-suppressor elements has demonstrated that ATF4 is upregulated in drug-resistant cells [114]. ATF2, which is another member of the ATF/cAMP-responsive element binding family, is phosphorylated via JNK activation following cisplatin treatment. Phosphorylated ATF2 plays a critical role in drug resistance by promoting p53-independent DNA repair [115]. We have previously shown that ATF4 is a cisplatininduced gene and is overexpressed in cisplatin-resistant cell lines [116]. ATF4 expression in human lung cancer cell lines correlated significantly with cisplatin sensitivity, and two stable transfectant ATF4-overexpressing derivatives of human lung cancer A549 cells were less sensitive to cisplatin than the parental cells. This is the first demonstration that ATF4 closely correlates with resistance to cisplatin. Cellular levels of ATF4 expression might aid the prediction of cisplatin efficacy; however, further study of the expression of ATF4 target genes is necessary to clarify the relationship between ATF4 expression and cisplatin resistance. Zinc-Finger Factor 143 (ZNF143) ZNF143 is a zinc-finger transcription factor and is the human homologue of selenocysteine tRNA gene-transcription activating factor (Staf), which was identified originally in the frog. Staf is involved in transcriptional regulation of snRNA type and mRNA promoters transcribed either by RNA polymerase II or III [117]. Two human Staf homologues, ZNF143 and ZNF76, were recently isolated; these are 84 and 64% identical to Xenopus Staf, respectively [118]. ZNF143 is required for transcriptional activation of



selenocysteine transfer RNA, which mediates the incorporation of selenocysteine into selenoproteins, such as glutathione peroxidase and thioredoxin reductase [119]. We recently characterized one cisplatin-inducible gene, the mitochondrial ribosomal protein S11 (MRP S11) gene [53], which is a component of the ribosomal small subunit and binds to 12S rRNA [120]. Although there is no evidence that MRP S11 is directly related to DNA damage signals, it has been shown that the apoptosis-related protein DAP3 is a component of the small subunit of the mitochondrial ribosome (mitoribosome) [121]. This suggests that the mitoribosome, with MRP S11 as one of the constituents, might be involved in the apoptotic pathway. The Staf binding site is located in the promoter region of the MRP S11 gene. Functional analysis of the MRP S11 promoter showed that ZNF143 regulates both basal and cisplatin-inducible promoter activities. Expression of the ZNF143 gene was upregulated, while ZNF76, which is another human homologue of Staf, was downregulated by cisplatin treatment in cancer cells. We also found that γ-irradiation and anticancer agents, such as etoposide and adriamycin, induced the expression of ZNF143. Furthermore, ZNF143 preferentially recognizes cisplatin-modified DNA, as is YB-1 [53]. It is important to investigate whether elevated expression of ZNF143 induces cisplatin resistance and to identify the molecules interacting with ZNF143. Mitochondrial Transcription Factor A (mtTFA) Mitochondria are the major site of ROS production in eukaryotic cells. The accumulation of ROS, which causes oxidative damage to the mitochondrial DNA (mtDNA), has been implicated in aging, cancer and various degenerative diseases [122]. mtDNA is more susceptible to oxidative damage than genomic DNA because of its lack of nucleosome structures, and mainly contains an oxidized form of the guanine base 8-oxo-7, 8-dihydroguanine (8-oxo-dG) [123]. Moreover, mtDNA might easily form cisplatinadducts similar to 8-oxo-dG induced oxidative stress. mtTFA is a member of the HMG-box protein family [124] that stimulates the transcription of mitochondrial genes by binding to the mitochondrial D-loop region. Nuclear HMG-box proteins, including HMG1/HMG2, are ubiquitous Table 3.

in higher eukaryotic cells and bind preferentially to cisplatindamaged DNA [48, 49]. mtTFA is essential not only for mitochondrial gene expression but also for mtDNA maintenance and repair [125]. Additionally, increased apoptosis has been observed in mtTFA-knockout animals, suggesting that mtTFA plays an important role in apoptosis [125]. We have previously demonstrated that mtTFA binds preferentially to oxidatively damaged DNA containing 8oxoguanine in addition to cisplatin modified DNA [126], whereas HMG1/HMG2 does not bind. Furthermore, the binding affinity of mtTFA for oxidized DNA is higher than that of mtMYH, which has DNA glycosylase activity and protects mtDNA from the mutagenic effects of oxidized DNA. We examined the number of cisplatin-targeted sequences in mtDNA from databases (NCBI; National Center for Biotechnology Information, and UCSC Genome Browser) and found that cisplatin-targeted sequences, such as Gstretch sequences, are more numerous in humans and gorillas than in rodents, frogs and flies. Interestingly, G-stretch sequences appear much more frequently in mtDNA than in nuclear DNA in humans (Table (3)). These observations suggest that mitochondria might be the main targets of cisplatin in human cancer cells. We previously showed that p53 physically interacts with mtTFA in mitochondria [127]. Binding of mtTFA to cisplatin-modified DNA was significantly enhanced by p53, similar to HMG1, whereas binding to oxidized DNA was inhibited. Thus, the interaction of p53 with mtTFA might contribute to cisplatin-induced apoptosis. The amount of mtTFA protein was also increased after cisplatin treatment [127]. Moreover, there is a Stafbinding site in the promoter region of the mtTFA gene, indicating that mtTFA is upregulated by the transcription factor ZNF143 during cisplatin treatment (data not shown). These findings suggest that mtTFA might act as a pivotal decision center in mechanisms of protection from cisplatininduced apoptosis, and could become a potential target for cancer chemotherapy. Other Transcription Factors Activator protein-1 (AP-1) is a transcription factor that induces various genes involved in cell proliferation,

Number of Cisplatin-Targeted DNA Sequences in Mitochondrial DNA

GG

AG

GGG

GGGG

GGGGG

Total number of mtDNA

Accession number

Human (Expectation) (Nuclear DNA)

2,202 2,071 1,919±319

2,233 2,071 2,292±101

703 518 501±77

250 129 118±25

85 32 35±14

16,565

AY255136

Gorilla Rat Mouse Xenopus Drosophila

2,137 1,696 1,501 1,536 615

2,185 2,041 2,015 2,174 1,332

667 440 346 331 98

232 113 83 72 26

77 36 22 9 9

16,364 16,300 16,300 17,553 16,019

NC_001645 NC_001665 AJ512208 M10217 NC_001322

Expectation indicates the probable number of each DNA sequence in human mitochondrial DNA. Nuclear DNA indicates the average of numbers of cisplatin-targeted DNA sequence in human nuclear DNA, which encodes each gene such as Sp1 (NM_138473), YB-1 (NM_004559), ZNF143 (NM_003442) and collagen type-I α2 (NM_000089) by way of example.

24


differentiation, tumor invasion and apoptosis [128]. A recent study has shown that an adenovirus expressing a dominantnegative form of AP-1, lacking DNA binding capability, is able to selectively inhibit cisplatin resistance [129]. Furthermore, downregulation of c-Jun and c-fos, which are components of the AP-1 transcription complex, by antisense oligonucleotides increases cisplatin sensitivity [130, 131]. cJun expression is also closely linked with cellular GSH content [130]. Nuclear factor-κB (NF-κB) is a transcription factor involved in the inflammatory and immune responses, which also functions as an anti-apoptotic molecule in TNF- and cancer therapy-induced apoptosis [132]. Moreover, it has been reported recently that NF-κB activation via inhibition of the ERK signaling pathway increases resistance to cisplatin in human cervical carcinoma cells [133]. Oct1, which is a member of the POU (Pit-Oct-Unc) homeodomain family, is ubiquitously expressed and plays a role in activating the transcription of various genes [134]. Recently, Oct1 was shown to be induced after cells are treated with UV irradiation and anti-cancer agents, including cisplatin, etoposide, camptothecine and TAS-103 [135, 72]. The V-ATPase c subunit gene, pH regulator, is overexpressed in cisplatin-resistant cell lines [70] and is induced by treatment with anti-cancer agents in an Oct1-dependent manner [72]. We previously showed that intracellular pH is significantly higher in cisplatin-resistant cell lines than in sensitive parental cell lines, and that in vitro cisplatin-DNA cross-link formation is markedly enhanced in low pH conditions [70]. Therefore, intracellular pH is involved in drug sensitivity and Oct1 might play a critical role in intracellular pH regulation. Furthermore, HMG2, which recognizes cisplatin-modified DNA, functionally interacts with the octamer transcription factors Oct1, Oct2 and Oct6 to enhance transcriptional activity [136]. Although there is no direct evidence to implicate Oct1 expression with resistance to cisplatin, these data indicate that Oct1 is potentially involved in drug resistance. Sp1 is a member of the C2-H2 zinc-finger family and was one of the first transcription factors to be identified in mammalian cells. Sp1 binds to GC boxes within promoter regions and regulates various genes, including housekeeping genes and genes involved in cell growth [137]. It has been previously shown that Sp1 regulates nitric oxide (NO)induced expression of the DNA-dependent protein-kinase catalytic subunit (DNA-PKcs), which is one of the key enzymes involved in the repair of double-stranded DNA breaks, to protect cells from DNA damaging agents such as X-ray radiation, adriamycin, bleomycin and cisplatin [138]. Interestingly, Sp1 and Oct1 also bind to the promoter of the human thioredoxin reductase 1 gene, which has antioxidant and redox regulatory functions that are involved in resistance to cisplatin [139]. Hypoxia, acidosis and a transient decrease in intracellular pH are common characteristics of solid tumors [68]. Tumor cells can survive under severely energy-deficient and acidic conditions, having developed several mechanisms to escape from cellular acidosis such as pH regulators [68]. One of the cellular pH regulators is the proton pump V-ATPase; its expression is thought to be regulated by Sp1 in addition to

Torigoe et al.

Oct1 [69, 72]. We have also shown that the DNA binding activity of Sp1 and its interaction with TBP are increased in low pH conditions [140]. Therefore, it is favorable for Sp1 to function well at low pH, enabling the cell to grow rapidly. A recent report from Wang et al. has shown that strong Sp1 expression is detectable in human gastric cancers and might be a significant predictor of survival [141]. Sp1 might thus be involved in cisplatin resistance and be a potentially promising molecular target for cancer chemotherapy. SUMMARY This review has focused on the transcription factors involved in the sensitivity of solid tumors to cisplatin. Transcription factors are DNA binding proteins, so it is possible that they are able to recognize DNA damage and participate in DNA repair action. Several transcription factors are activated by cisplatin treatment. We have previously reported various transcription factors—including YB-1, CTF2, ATF4, ZNF143 and mtTFA—that act as inducing genes involved in drug resistance and DNA repair. YB-1 and ZNF143 might directly participate in DNA repair reactions, because both transcription factors can preferentially recognize DNA damage. Furthermore, transcription factors with upregulated expression in cisplatin-resistant cells, such as YB-1, ATF4, ZNF143, Oct1 and Sp1, might also control the expression of the proteins that are involved in redox processes induced by cisplatin. We believe that transcription factors might represent a potential target for cancer chemotherapy. However, only nuclear hormone receptors are widely recognized as good targets for chemotherapy against hormone-dependent tumors. Molecular interactions with transcription factors induced by DNA damage are thought to be important for either survival or apoptosis, suggesting that these interactions might be also promising targets for cancer chemotherapy. Further studies to identify DNA damage-induced transcription factors and characterize functions of these factors might allow us to understand cisplatin sensitivity and to develop novel molecular-targeted drugs in future. ACKNOWLEDGEMENTS This work was supported in part by Mext. Kakenhi (13218132) and AstraZeneca Research Grant 2002. ABBREVIATIONS ASK1

= Apoptosis signal-regulating kinase 1

ATF4

= Activating transcription factor 4

ATR

= Ataxia telangiectasia mutated and Rad3related protein

CTF/NF-I = CTF/nuclear factor I CTF2

= CCAAT-binding transcription factor 2

ER

= Endoplasmic reticulum

ERK

= Extracellular signal-regulated kinase

GPX

= Glutathione peroxidase

GSH

= Glutathione

GST

= Glutathione S-transferase


Curr. Med. Chem. – Anti-Cancer Agents, 2005, Vol. 5, No. 1 25 [20]

HMG

= High-mobility group

JNK

= c-Jun N-terminal kinase

MAPK

= Mitogen-activated protein kinase

MDR1

= Multidrug resistance 1

[22]

MMR

= Mismatch repair

[23]

MRP2

= Multidrug resistance-associated protein 2

[24]

mtDNA

= Mitochondrial DNA

mtTFA

= Mitochondrial transcription factor A

NER

= Nucleotide-excision repair

NF-κB

= Nuclear factor-κB

Nrf1

= Nuclear-factor erythroid 1

ROS

= Reactive oxygen species

Staf

= Selenocysteine tRNA gene-transcription activating factor

TBP

= TATA-binding protein

TrxR

= Thioredoxin reductase

UV

= Ultraviolet

V-ATPase = Vacuolar H+-ATPase YB-1

= Y-box binding protein-1

ZNF143

= Zinc-finger factor 143

[21]

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